I think the main reason lies in the fact that the organic anion transporting polypeptides (OATPs in humans, Oatps in rodents), which have been the topic of my research during the past years, have been recognized by pharmacologists and the drug companies to be important for drug absorption and distribution. In addition, we have introduced a new nomenclature and classification system for the OATPs which has been widely accepted and is cited by most researchers publishing on OATPs.

Transport proteins always fascinated me, perhaps because being membrane proteins they were more challenging to work with than soluble proteins. I started to work on transport proteins during my Ph.D. dissertation with Prof. H. Murer in Zurich and extended these functional studies as a postdoc with Prof. E. M. Wright at UCLA where I learnt the powerful technique of expression cloning. We then used expression cloning in the lab of Prof. P.J. Meier in Zurich for the cloning of the first sodium-dependent bile acid transporter (Ntcp) and the first sodium-independent Oatp from rat liver.

We know today that there are 11 OATPs in humans, which can be grouped into six families. Of these 11 OATPs, the six members of families 1 and 2 have been extensively characterized, whereas only a few publications exist for the members of families 3-6. The best characterized members are the liver-specific OATP1B1 and OATP1B3, as well as OATP1A2, which is strongly expressed in brain. These OATPs are polyspecific carriers that mediate transport of a variety of amphipathic organic compounds including endo- and xenobiotics and numerous drugs. These OATPs are important for excretion of potentially toxic compounds and thus involved in overall body detoxification. The role of the members of families 3-6 is less clear. These OATPs are less well characterized and we do not know whether they all are transporters under normal physiological conditions. People often forget that just because a protein transports a certain compound under in vitro conditions, this does not necessarily mean that this compound is transported by the same protein in vivo. Therefore, it remains to be demonstrated whether all the OATPs indeed are transport proteins and what substrates they might transport under normal physiological conditions.

Until a few years ago, pharmacologists assumed that most amphipathic compounds, which include numerous drugs, would cross cell membranes and thus epithelial layers like the gut wall, the blood-brain barrier, hepatocytes, and renal tubular cells by simple diffusion. Since we and others showed that the OATPs and other transporters play an important role in mediating uptake of numerous drugs into cells, these transporters have become very interesting for pharmacologists and drug companies. A detailed understanding of the structure and function of these transporters will help to better understand the molecular mechanism of drug actions and interactions at the uptake level.

In 1994 we isolated the first Oatp from rat liver by expression cloning in the Division of Clinical Pharmacology in Zurich. In the meantime, over 80 members of the Oatp gene superfamily have been identified in 13 different species. In 1996 we published the first paper demonstrating that an individual Oatp can transport a wide variety of differentially charged lipophilic organic compounds including endogenous and exogenous organic anions, neutral steroids, and organic cations. Since then, this multispecificity has been demonstrated for many OATPs/Oatps in several species. Nevertheless, there are substrates that are preferentially transported by individual Oatps. The mechanism of this multispecificity as well as the abilities of the OATPs/Oatps to distinguish between different compounds is the focus of my present research in the Department of Pharmacology, Toxicology and Therapeutics of the Kansas Medical Center.

With respect to drug delivery, we know that Oatps play a role in the uptake of certain drugs into liver and that they are potential targets for drug-drug interactions. They are also responsible for the first-pass elimination of clinically relevant compounds. In the future, we might be able to use OATP-specific inhibitors to improve the bioavailability of certain compounds that are removed by OATPs. Furthermore, certain organ-specific OATPs might be used for an organ-specific delivery of drugs.

  Where do you see this research going 10 years from now?

At the moment people investigate the implications of polymorphisms of OATPs on drug absorption and distribution. In 10 years, I expect that we will know more about structure-function relationships of OATPs and perhaps have determined their tertiary structure. We then should be able to predict and prevent drug-drug interactions, design OATP-specific substrates and/or inhibitors, and use our knowledge on OATPs for a more rational drug design and delivery.

Bruno Hagenbuch, Ph.D.
Department of Pharmacology, Toxicology and Therapeutics 
University of Kansas Medical Center
Kansas City, KS, USA